Biogerontology最新文献

Sarcopenia and cancer cachexia are two life-threatening conditions often misdiagnosed. The skeletal muscle is one of the organs most adversely affected by these conditions, culminating in poor quality of life and premature mortality. In addition, it has been suggested that chemotherapeutic agents exacerbate cancer cachexia, as is the case of doxorubicin. Herein, we sought to investigate markers of inflammation and neuromuscular junction (NMJ) remodeling during aging and in response to cancer or cancer with chemotherapy. To address this, we utilized female rats across three age groups - young, adult, and old - to examine age-related changes, with old rats serving as a sarcopenia model. Additionally, a chemically-induced breast cancer (BCa) model was implemented in female adult rats, both without (adult BCa) or with doxorubicin administration (adult BCaDOX), to study cancer cachexia. The atrophy of the gastrocnemius muscle was observed in old, adult BCa and adult BCaDOX rats compared to adult ones. No signs of inflammation or NMJ impairment were observed in adult BCa or adult BCaDOX rats, except for the low levels of the subunit α1 of the acetylcholine receptor in adult BCaDOX rats compared to adult ones. In contrast, old rats presented high serum levels of interleukin 6, brain-derived neurotrophic factor (BDNF) and calcitonin gene-related peptide compared to young rats. In the gastrocnemius muscle, BDNF levels were decreased in old rats compared to adult rats, suggesting impaired skeletal muscle regeneration upon age-induced damage. The BDNF muscle levels were inversely correlated with its levels in circulation in adult and old rats. Hence, this work highlights BDNF as a specific biomarker of age-induced skeletal muscle atrophy, at least, in the differential diagnosis against cancer- or cancer with chemotherapy-induced muscle wasting.

The American Heart Association's (AHA) Life's Essential 8 (LE8) metrics provide a framework for assessing cardiovascular health (CVH). This study evaluates the relationship between CVH levels from LE8 and mortality risk, considering biological aging's role. Using data from the NHANES non-CVD adult population, CVH scores were categorized as low (< 50), moderate (50-79), and high (≥ 80) per AHA guidelines. Cox regression model assessed the impact of CVH levels on all-cause and cardiovascular mortality, while examining four aging indicators as mediators. RCS explored the relationships between CVH scores and mortality risk. The model's performance was evaluated using nine machine learning algorithms, with SHAP analysis on the best model to determine CVH score components' importance. Cox regression showed that all-cause mortality rates decreased by 35% for moderate and 54% for high CVH groups compared to low CVH. The high CVH group had a 59% lower cardiovascular mortality rate. Each unit increase in CVH score reduced all-cause and cardiovascular mortality to 0.98 times. RCS analysis revealed a nonlinear trend between CVH scores and mortality risk. Biological aging indicators significantly mediated the CVH-mortality relationship, with PhenoAge (21.57%) and KDM-Age (20.33%) showing the largest effects. The XGBoost model outperformed others, with SHAP analysis ranking CVH components: physical activity, nicotine, blood pressure, BMI, lipids, healthy eating index, blood glucose, and sleep. Higher CVH levels correlate with reduced all-cause and cardiovascular mortality risk, with biological aging mediating these effects. Adhering to AHA's LE8 metrics is recommended to enhance life expectancy in the non-CVD population.

The collective detrimental impact of aged naive lymphocytes and thymus atrophy on the aging of the immune system can be mitigated by exercise. Hence, this research aims to explore the effects of three methods of water-based exercises on immune system aging and thymus atrophy in elderly rats. Thirty-two 24-month-old rats, with an average weight of 320 ± 5 g, were randomly allocated into four groups of endurance training (n = 8), resistance training (n = 8), combined training (n = 8), and control (n = 8).The training protocols (10 weeks) were conducted four times a week in a container measuring 50 × 50x100 cm filled with water at 30 ± 1 °C. The evaluation of naïve and memory T lymphocytes was conducted for the intervention groups based on the expression or lack of expression of the CD28 and CD57 markers in the subsets of CD4 + and CD8 + T cells. Naïve T cells were represented by CD28 + CD57- T lymphocytes, memory T cells were represented by CD28- CD57- T lymphocytes, aged naïve T cells were indicated by CD28 + CD57 + lymphocytes, and aged memory T cells were represented by CD28- CD57 + lymphocytes. The findings of the study showed that all three exercise protocols resulted in a significant decrease in levels of memory CD8, aged CD8, naive and naive CD4 and CD8, and aged memory, as well as an increase in levels of CD4, CD8, CD4 + , and naive CD8 when compared to the control group. It was observed that thymus atrophy, memory CD4, and aged CD4 had a significant decrease only in the combined exercise group compared to the control group, with no significant differences observed in these indicators for the resistance and endurance groups. Furthermore, the ratio of CD4 to CD8 remained unchanged across all groups. The findings of this study suggest greater efficacy of combined training in enhancing specific health indicators of cell immunity among elderly populations. Moreover, engaging in water exercises of all three types of combined, resistance, and endurance training are deemed safe activities for older individuals to bolster their immune system and mitigate the aging process of T cells.

Aging is associated with a marked increase in cardiovascular diseases, such as myocardial infarction (MI). Cellular senescence is also a crucial factor in the development of age-related MI. Matrix metalloproteinases (MMPs) interaction with cellular senescence is a critical determinant of MI development and outcomes, most notably in the aged heart. After experiencing a heart attack, senescent cells exhibit a Senescence-Associated Secretory Phenotype (SASP) and are involved in tissue regeneration and chronic inflammation. MMPs are necessary for extracellular matrix proteolysis and have a biphasic effect, promoting early heart healing and detrimental change if overexpressed shortly. This review analyses the complex connection between senescence and MMPs in MI and how it influences elderly cardiac performance. Critical findings suggest that increasing cellular senescence in aged hearts elevates MMP activity and aggravates extended ventricular remodeling and dysfunction. Additionally, we explore potential therapeutics that address MMPs and senescence to enhance old MI patient myocardial performance and regeneration.

Alzheimer's disease (AD) and osteoporosis (OP) pose distinct but interconnected health challenges, both significantly impacting the aging population. AD, a neurodegenerative disorder characterized by memory impairment and cognitive decline, is primarily associated with the accumulation of abnormally folded amyloid beta (Aβ) peptides and neurofibrillary tangles in the brain. OP, a skeletal disorder marked by low bone mineral density, involves dysregulation of bone remodeling and is associated with an increased risk of fractures. Recent studies have revealed an intriguing link between AD and OP, highlighting shared pathological features indicative of common regulatory pathophysiological pathways. In this article, we elucidate the signaling mechanisms that regulate the pathology of AD and OP and offer insights into the intricate network of factors contributing to these conditions. We also examine the role of bone-derived factors in the progression of AD, underscoring the plausibility of bidirectional communication between the brain and the skeletal system. The presence of amyloid plaques in the brain of individuals with AD is akin to the accumulation of brain Aβ in vascular dementia, pointing towards the need for further investigation of shared molecular mechanisms. Moreover, we discuss the role of bone-derived microRNAs that may regulate the pathological progression of AD, providing a novel perspective on the role of skeletal factors in neurodegenerative diseases. The insights presented here should help researchers engaged in exploring innovative therapeutic approaches targeting both neurodegenerative and skeletal disorders in aging populations.

Spermatogenesis is finely regulated by histone methylation, which is crucial for regulating gene expression and chromatin remodeling. Functional studies have demonstrated that the histone lysine methyltransferases (KMTs) SETD1B, CFP1, SETDB1, G9A, and SETD2 play pivotal roles in spermatogenesis through establishing the key histone methylation marks, H3K4me3, H3K9me2, H3K9me3, and H3K36me3, respectively. This study aimed to evaluate the spatiotemporal expression of these KMTs and methylation marks as well as senescence-associated β-galactosidase (β-GAL), transcriptional activity, and apoptosis rates in mouse testes during biological aging. In accordance with these purposes, the following groups of Balb/C mice were created: young (1- and 2-week-old), prepubertal (3- and 4-week-old), pubertal (5- and 6-week-old), postpubertal (16-, 18-, and 20-week-old), and aged (48-, 50-, and 52-week-old). The β-GAL staining gradually increased from the young to the aged groups (P < 0.01). The SETD1B, G9A, SETDB1, and SETD2 protein levels increased in spermatogonia, early and pachytene spermatocytes, and Sertoli cells of the aged group (P < 0.05). In contrast, CFP1 protein level decreased in spermatogonia, pachytene spermatocytes, round spermatids, and Sertoli cells towards the older ages (P < 0.05). Moreover, H3K4me3, H3K9me2, H3K9me3, and H3K36me3 levels increased in the aged group (P < 0.05). There was also a significant reduction in apoptosis rates in seminiferous tubules of the pubertal, postpubertal, and aged groups (P < 0.01). Consequently, accumulation of histone methylation marks due to increased expression of KMTs in spermatogenic and Sertoli cells during testicular aging may alter chromatin reprogramming and gene expression, contributing to age-related fertility loss.

The growing prevalence of age-related cardiovascular diseases (CVDs) poses significant health challenges, necessitating the formulation of novel treatment approaches. GATA4, a vital transcription factor identified for modulating cardiovascular biology and cellular senescence, is recognized for its critical involvement in CVD pathogenesis. This review collected relevant studies from PubMed, Google Scholar, and Science Direct using search terms like 'GATA4,' 'cellular senescence,' 'coronary artery diseases,' 'hypertension,' 'heart failure,' 'arrhythmias,' 'congenital heart diseases,' 'cardiomyopathy,' and 'cardiovascular disease.' Additionally, studies investigating the molecular mechanisms underlying GATA4-mediated regulation of GATA4 and senescence in CVDs were analyzed to provide comprehensive insights into this critical aspect of potential treatment targeting. Dysregulation of GATA4 is involved in a variety of CVDs, as demonstrated by both experimental and clinical research, comprising CAD, hypertension, congenital heart diseases, cardiomyopathy, arrhythmias, and cardiac insufficiency. Furthermore, cellular senescence enhances the advancement of age-related CVDs. These observations suggested that therapies targeting GATA4, senescence pathways, or both as necessary may be an effective intervention in CVD progression and prognosis. Addressing age-related CVDs by targeting GATA4 and senescence is a broad mechanism approach. It implies further investigation of the molecular nature of these processes and elaboration of an effective therapeutic strategy. This review highlights the importance of GATA4 and senescence in CVD pathogenesis, emphasizing their potential as therapeutic targets for age-related CVDs.

Aging women experience a significant decline of ovarian hormones, particularly estrogen, following menopause, and become susceptible to cognitive and psychomotor deficits. Although the effects of estrogen depletion had been documented in the prefrontal and somatosensory cortices, its impact on somatomotor cortex, a region crucial for motor and cognitive functions, remains unclear. To explore this, we ovariectomized young adult female rats and fed subsequently with phytoestrogen-free diet and studied the effects of estrogen depletion on the somato-sensory and motor cortices. Low serum estrogen was confirmed prior to biochemical and morphological analyses. Results revealed that estrogen depletion differentially affected the two cortical areas: all three estrogen receptors were downregulated in the somatosensory cortex, whereas in the somatomotor cortex, G-protein-coupled estrogen receptor 30 was upregulated, estrogen receptor α decreased, and estrogen receptor β remained unaffected. Intracellular dye injections revealed decreased dendritic spines on layer III and V pyramidal neurons of the somato-sensory cortex but increased in those of the motor cortex. These were accompanied by decrease and increase of excitatory postsynaptic density protein 95 respectively. Since dendritic spines receive excitatory inputs, these findings suggest that estrogen depletion changes the excitatory connectivity of the somato-sensory and motor cortices in opposite directions. Notably, estradiol replenishment reversed the dendritic spine increase in the somatomotor cortex, confirming the estrogen dependency of this effect. The differential influence of estrogen depletion on these two cortices could have contributed to the cognitive and psychomotor abnormalities in postmenopausal females.

If a shortened lifespan is evolutionarily advantageous, it becomes more likely that nature will strive to change it accordingly, affecting how we understand aging. Premature mortality because of aging would seem detrimental to the individual, but under what circumstances can it be of value? Based on a relative incremental increase in fitness, simulations were performed to reveal the benefit of death. This modification allows for continuous evolution in the model and establishes an optimal lifespan even under challenging conditions. As a result, shorter-lived individuals achieve faster adaptation through more frequent generational turnover, displacing longer-lived ones and likely providing a competitive advantage between species. Contrary to previous assumptions, this work proposes a mechanism by which early death, e.g., due to aging, may contribute to evolution.

Human populations are experiencing unprecedented growth and longevity with lingering knowledge gaps of the characteristics, mechanisms, and pathologies of senescence. Invasive measurements and long-term control conditions for longitudinal studies are infeasible, necessitating the need for surrogate animal models. Rats have short lifespans (2-3 years) with translatable cardiovascular systems, and Sprague Dawley microcirculatory preparations are key to studying the oxygen transport mechanisms critical to the loss of skeletal muscle function in aging. Here we present baseline physiological data of 61 male, Sprague Dawley rats at 3, 6, 12, 18, and 24 months of age. Anesthetized animals were surgically prepared for femoral arterial and venous cannulations, tracheal intubation, and exteriorization of the spinotrapezius muscle. Measurements included cardiovascular function, blood gases, and peripheral tissue interstitial oxygen tension (P_ISFO₂) using phosphorescence quenching microscopy. Intrinsic heart rates decreased with age without significant changes to blood pressure. Arterial oxygen tension declined 17% by 18 and 24 Months (p < 0.05) while p_ACO₂ and P_ISFO₂ were unchanged. Lactate was elevated at 12 and 18 Months along with an alkaline shift in blood pH. Heart rate and decreased p_AO₂ decoupled from p_ACO₂ are conserved phenomena in human aging. The continuity of resting P_ISFO₂ despite an anaerobic shift in metabolism may be due to declining mitochondrial function and dysregulation of the vascular response to hypoxemia, which are also present in aged humans. These physiological and microcirculatory data offer a useful experimental model for investigating the detailed changes in oxygen supply and demand that affect senescing skeletal muscles in rats and humans.